Gene Therapy:Frequently Asked Questions

Gene therapy is a therapeutic approach that targets abnormal genes with the goal of treating or preventing genetic diseases.

Researchers are testing several different gene therapy approaches including:

Gene Transfer – Used to address diseases caused by an error, or mutation, in a gene that makes the body unable to produce a functioning protein, like dystrophin. Through gene transfer, a functional version of the mutated gene is delivered to cells in the body. The new gene allows cells to make a working form of the protein at sufficient levels to make up for the missing or abnormal protein that was responsible for causing the disease.

Gene Inhibition – Used to turn off “rogue” genes with abnormal activity that causes diseases, such as cancer and some inherited disorders. For instance, one of the major goals of this approach in cancer is to stop the activity of genes that encourage the growth of abnormal cells.

Gene Editing – Also known as genome editing. A type of genetic engineering used to directly remove, add or replace the mutated DNA in cells.

Gene transfer is a type of gene therapy. Gene transfer attempts to address the root cause of certain diseases by introducing a new, functional gene to take over for the non-functioning, mutated gene causing the disease. This new gene is then utilized by the body to produce functioning proteins that the mutated gene was unable to make. If successful, gene transfer may help many patients with diseases that are difficult or even impossible to address with traditional approaches.

In gene therapy, modified viruses are often used as carriers to deliver a new, functional gene to cells in the body. These modified viruses are called viral vectors. Adeno-associated virus, or AAV, is a small, naturally-occurring virus that is modified for use and is attractive to use for gene transfer for several reasons:

• It is not currently known to cause illness

• While it can introduce a new, functional gene to cells, it is not known to alter a person’s original DNA

• Preclinical work has shown that AAV can reach selected tissues and cell types quickly and effectively

There are several types of AAV vectors, which differ based on the proteins that make up their outer shells, or capsids. Different types of AAV have preferences for different tissues and cell types.

Gene transfer approaches typically utilize viruses, or viral vectors, like AAV that can package the new gene and deliver it to cells. For diseases like Duchenne that affect many different parts of the body, viral vectors carrying the new gene may be delivered through a vein (intravenous or IV) and travel through the bloodstream to reach different tissues and cell types throughout the body. A promoter is delivered along with the new gene to tell it to turn on only in desired tissues, such as skeletal, diaphragm and heart muscles.

Microdystrophin is a synthetic form of the dystrophin gene that was designed because the natural, full-size dystrophin gene is too big to fit into an AAV vector. Microdystrophin retains the most critical components of full-size dystrophin yet fits into an AAV vector.

Researchers are currently studying several different microdystrophin genes for their potential to drive production of functional versions of dystrophin protein in muscles of the body.

While the results from preclinical studies are promising, there may be risks associated with treatment, such as immune reactions to the viral vector or other side effects. It is not yet known how often side effects might occur or how severe, serious or long-lasting they may be. Clinical trials are needed to best evaluate both the safety and efficacy of gene transfer candidates in Duchenne.

Importantly, it is known that some patients may already have developed antibodies against AAV because it is a naturally-occurring virus. If their antibody levels are high, gene transfer using AAV may be unsafe and/or unlikely to work, so such patients are currently excluded from receiving AAV vectors in clinical trials. Researchers are currently working on solutions for this challenge.

The safety and efficacy of gene transfer and the duration of its potential effect in Duchenne still need to be determined through human clinical trials. Gene transfer has not yet been approved as a therapy for Duchenne by any regulatory authority in the world.

While further investigation is needed, preclinical studies have shown that gene transfer may be a way to slow or halt Duchenne disease progression.

Because patients who receive one dose of AAV-mediated gene transfer develop immunity against AAV, giving a second dose of an AAV vector may be unsafe and/or unlikely to work.

Accordingly, patients who have received AAV-mediated gene transfer already may not be able to receive another dose or to participate in another gene transfer trial that uses AAV. Scientists are working on approaches that may allow AAV-mediated gene transfer to be administered more than once, but it will take time to know if this goal can be achieved.

While the aim of gene transfer is to slow or halt the progression of Duchenne, it is not intended to repair existing muscle damage that occurred before treatment. Currently, researchers believe that gene transfer may only impact muscles that still have function. Muscle damage and the buildup of scar tissue (fibrosis) in patients with advanced disease may limit the response to treatment.

While preclinical studies have demonstrated that microdystrophin gene transfer may slow or halt disease progression, it is not intended to repair existing muscle damage that occurred before treatment, such as fibrosis (scar tissue). Ultimately, treatment for Duchenne may involve a combination of therapies that address both the underlying genetic cause and the many different symptoms that result from the disease.

Clinical trial activities for microdystrophin are currently underway. Talk to your doctor to find out more information.